In mammals, damaged neuron cells are not regenerated and their damage causes neurodegenerative disorders, such as stroke, spinal cord injury, Parkinson's and Alzheimer's diseases (J. Neurochem. 2005, 93, 1412 and Neuron 2003, 39, 889). Recent advances in stem cell biology offer the prospect of new therapeutic approaches for treating a number of diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer (Committee on the Biological and Biomedical Applications of Stem Cell Research, Stem Cells and the Future of Regenerative Medicine 2002, the National Academies Press, Washington, D.C). However, these approaches require identification of renewable cell sources of engraftable functional cells, precise control of differentiation, suppression of the immune response of differentiated cells and prevention of cancer induction by undifferentiated stem cells (Curr. Top. Med. Chem. 2005, 5, 383 and Biotechnol. 2004, 22, 833).
Alternatively, chemical approaches using small molecules that induce neuron differentiation from easily available cells or tissues such as myoblasts or muscle fibers have great potential (Nature 2002, 416, 485; Nature 2002, 418, 41 and Science 2004 303, 1669). Several examples of the differentiation of mammalian cells into specific cell types using small molecules have been reported. For example, osteoblasts are differentiated from embryogenic mesoderm fibroblasts (C3H10T1/2) using Purmorphamine (J. Am. Chem. Soc. 2002, 124, 14520). In addition, cardiac muscle cells and neuron cells are differentiated from embryonic stem cells (P19) by Cardiogenols and TWS-119, respectively (J. Am. Chem. Soc. 2004, 126, 1590 and Proc. Natl. Acad. Sci. USA 2003, 100, 7632). Thus, compounds that induce neuron differentiation may be very useful for producing a source of neuron cells for trials of transplantation therapies for neurodegenerative disorders.
Therefore, there is a need in the art for compositions and methods for inducing differentiation of easily available cells or tissues into neuron cells. The developed small molecule inducers not only provide valuable information on the molecular mechanism of neuron differentiation but may also, ultimately, allow in vivo neuron regeneration. The present invention satisfies these and other needs.